Role of the dopamine and serotonin transporters in addiction: prediction of the abuse potential of new psychoactive substances

Abstract

Drugs of abuse are largely controlled and prohibited, however the emergence of New Psychoactive Substances (NPS) starts to be a threat to global health. NPS are created based on minor modifications on the structure of well-known drugs that can lead to new products avoiding current legislation, and have the same or even greater psychoactive and stimulant effects than classical drugs of abuse. Among NPS, synthetic cathinones are -keto analogues of amphetamine, that mimic the effects of traditional psychostimulants such as cocaine or MDMA. The aim of the present study was to review the role of the dopamine transporter and serotonin transporter in addiction, especially regarding NPS, and describe the pharmacological profile of 7 novel synthetic cathinones, as well as to compare them with standard psychoactive or prescribed compounds such as cocaine, MDMA, or paroxetine. To evidence the direct blockade of dopamine and serotonin reuptake by these novel synthetic cathinones, HEK293 cells were used to carry out monoamine uptake inhibition assays. Our study demonstrated that all 7 new compounds potently inhibit dopamine uptake and had very little effect on 5-HT uptake inhibition. Consequently, all these new substances possess high hDAT/hSERT ratios, even greater than cocaine. This selectivity may have a key role in their predictable abuse potential, since a higher ratio hDAT/hSERT may allow us to predict a higher addictive potential, and thus, a threat to public health.